Patent GB-1123333-A (GB)
Title: Cephalosporin compounds
IPC: C07D501/32
Filed: 1966-01-17
Abstract: The invention relates to N-protected aminoacylcephalosporin compounds, of formula <F\1> wherein R1 is acetoxy or pyridino; R2 is -OH when R1 is acetoxy, and -O- when R1 is pyridino; R3 is C1 to C4 alkyl, C3 to C6 cycloalkyl, phenyl, naphthyl, thienyl, furyl, benzothienyl, benzofuryl, indolyl, or pyridyl; R4 is H, methyl or ethyl; m and n are 0 or 1, R5 is H, C1 to C4 alkyl or phenyl; R6 is H, phenyl substituted C1 to C4 alkyl, C1 to C4 alkyl, or phenyl; R7 is H, C1 to C4 alkyl, C1 to C4 alkoxy, or phenyl; or R6 and R7, together with the associated carbon atoms, complete a naphthalene or benzene ring structure; or R5 and R7, together with the interconnecting carbon atoms, form a C5 to C7 cycloaliphatic ring; and to salts thereof with pharmaceutically acceptable cations.  The invention also relates to a process for preparing 7 - aminoacylcephalosporin compounds of formula <F\2> wherein R1, R2, R4, m and n are as defined above, by hydrolysing the inventive compounds at a pH below 5.0, to remove the amine protecing group, optionally forming a salt of the said cephalosporin compound with a pharmaceutically acceptable cation. In the above compounds, one or more of the groups R1 and R3 to R7 may optionally be substituted by: e.g. halo, -OH, -NO2, C1 to C4 alkyl, -CF3, CH3O-, CH3S-, -CN, hydroxymethyl, b -hydroxyethyl, acetyl, or acetamido. Pharmaceutically ethyl, acetyl, or acetamido.  Pharmaceutically acceptable cations include:  Na, K, NH4, substituted ammonium, Ca, Ba, procaine, guinine, and dibenzylethylenediamine.  The inventive compounds are prepared by reacting an N-protected amino-acid, either in the form of a mixed anhydride or directly, in the presence of a carbodiimide or a carbonyl diimidazole, with the appropriate 7-aminocephalosporin nucleus.  The reactants are either employed as their amine salts, or else a small quantity of a tertiary amine is included in the reaction mixture.  The reaction is suitably performed in mixed aqueous-organic solvent, from which the product may be isolated by nonmiscible organic solvent extraction, or evaporation to dryness and recrystallization.  The N-protecting group in the amino-acid reactant may be formed by condensing the amino-acid with a b -dicarbonyl compound, particularly a b -diketone, a b -keto ester, or another such b -dioxocompound.  Hydrolysis to remove this group may be with inorganic or sufficiently strong organic acid, at about pH 2 in aqueous solution at ambient temperature. Examples are given for the preparation of 7 - D - a  - phenylglycylcephalosporanic acid and 7 - (D - a  N[2-(4 - keto - 2 - propenyl)]-aminophenylacetamido) cephalosporanic acid.  Sodium methyl 3-(a -carboxybenzylamino)crotonate is prepared by reacting D-a -phenylglycine with methyl acetoacetate in a hot slurry of benzene and aqueous sodium hydroxide.  Potassium D - N - [2 - (4 - keto - 2 - propenyl)-phenylglycine is prepared by reacting D-phenylglycine with acetylacetone in methanolic potassium hydroxide.  Pharmaceutical compositions comprise the 7-aminoacylcephalosporins having the second of the above formulae together with a pharmaceutical carrier.